ClinVar Miner

Submissions for variant NM_001148.6(ANK2):c.10362G>C (p.Arg3454Ser) (rs55726422)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000519386 SCV000618114 uncertain significance not specified 2017-10-23 criteria provided, single submitter clinical testing A variant of uncertain significance has been identified in the ANK2 gene. The R3454S variant has not been published as pathogenic or been reported as benign to our knowledge. This variant has been observed in 11/24012 (0.05%) alleles from individuals of African ancestry in large population cohorts (Lek et al., 2016). The R3454S variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. However, this substitution occurs at a position that is not conserved across species and serine (S) is the wild-type residue at this position in at least one mammalian species. In silico analysis predicts this variant likely does not alter the protein structure/function.
Invitae RCV000690898 SCV000818629 uncertain significance Long QT syndrome 2020-10-07 criteria provided, single submitter clinical testing This sequence change replaces arginine with serine at codon 3454 of the ANK2 protein (p.Arg3454Ser). The arginine residue is weakly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is present in population databases (rs55726422, ExAC 0.06%), and has an allele count higher than expected for a pathogenic variant (PMID: 28166811). This variant has not been reported in the literature in individuals with ANK2-related disease. ClinVar contains an entry for this variant (Variation ID: 449744). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000519386 SCV001363532 likely benign not specified 2019-01-28 criteria provided, single submitter clinical testing Variant summary: ANK2 c.10362G>C (p.Arg3454Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 276470 control chromosomes (gnomAD). The observed variant frequency is approximately 13 fold of the estimated maximal expected allele frequency for a pathogenic variant in ANK2 causing Arrhythmia phenotype (1e-05), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.10362G>C in individuals affected with Arrhythmia and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.

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